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"Treatment Failure"
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Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease
Among patients with type 2 diabetes and stage 4 chronic kidney disease, bardoxolone methyl, as compared with placebo, did not reduce the risk of end-stage renal disease or cardiovascular death. Cardiovascular events in the bardoxolone group prompted trial termination.
Type 2 diabetes mellitus is the most important cause of progressive chronic kidney disease in the developed and developing worlds. Various therapeutic approaches to slow progression, including restriction of dietary protein, glycemic control, and control of hypertension, have yielded mixed results.
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Several randomized clinical trials have shown that inhibitors of the renin–angiotensin–aldosterone system significantly reduce the risk of progression,
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although the residual risk remains high.
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None of the new agents tested during the past decade have proved effective in late-stage clinical trials.
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Oxidative stress and impaired antioxidant capacity intensify with the progression of chronic kidney disease.
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In . . .
Journal Article
Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease
Standard treatment for GVHD is glucocorticoids, but for glucocorticoid-refractory GVHD, no intervention has emerged as standard second-line treatment. This trial with 329 patients compared ruxolitinib with control (chosen from among 10 possible therapies) in patients with glucocorticoid-refractory chronic GVHD. Response at week 24 was 50% with ruxolitinib as compared with 26% with control therapy.
Journal Article
Maximizing Psychotherapy Outcome beyond Evidence-Based Medicine
Despite evidence that psychotherapy has a positive impact on psychological disorders, 30% of patients fail to respond during clinical trials, and as many as 65% of patients in routine care leave treatment without a measured benefit. In addition, therapists appear to overestimate positive outcomes in their patients relative to measured outcomes and are particularly poor at identifying patients at risk for a negative outcome. These problems suggest the need for measuring and monitoring patient treatment response over the course of treatment while applying standardized methods of identifying at-risk cases. Computer-assisted methods for measuring, monitoring, identifying potential deteriorators, and providing feedback to clinicians are described along with a model that explains why feedback is likely to be beneficial to patients. The results of 12 clinical trials are summarized and suggest that deterioration rates can be substantially reduced in at-risk cases (from baseline rates of 21% down to 13%) and that recovery rates are substantially increased in this subgroup of cases (from a baseline of 20% up to 35%) when therapists are provided this information. When problem-solving methods are added to feedback, deterioration in at-risk cases is further reduced to 6% while recovery/improvement rates rise to about 50%. It is suggested that the feedback methods become a standard of practice. Such a change in patterns of care can be achieved through minimal modification to routine practice but may require discussions with patients about their clinical progress.
Journal Article
Access and response to direct antiviral agents (DAA) in HIV-HCV co-infected patients in Italy: Data from the Icona cohort
Real-life data on access and response to direct antiviral agents (DAA) in HIV-HCV coinfected individuals are lacking.
HCV viremic, HIV-positive patients from Icona and Hepaicona cohorts naïve to DAA by January 2013 were included. Access and predictors of starting DAA were evaluated. Switches of antiretroviral drugs at starting DAA were described. We calculated sustained virological response (SVR12) in those reaching 12 weeks after end-of-treatment (EOT), and defined treatment failure (TF) as discontinuation of DAA before EOT or non-SVR12. Statistical analyses included Kaplan-Meier curves, univariable and multivariable analyses evaluating predictors of access to DAA and of treatment outcome (non-SVR and TF).
2,607 patients included. During a median follow-up of 38 (IQR:30-41) months, 920 (35.3%) patients started DAA. Eligibility for reimbursement was the strongest predictor to access to treatment: 761/1,090 (69.8%) eligible and 159/1,517 (10.5%) non-eligible to DAA reimbursement. Older age, HIV-RNA≤50 copies/mL were associated to faster DAA initiation, higher CD4 count and HCV-genotype 3 with delayed DAA initiation in those eligible to DAA reimbursement. Up to 28% of patients (36% of those on ritonavir-boosted protease inhibitors, PI/r) underwent antiretroviral (ART) modification at DAA initiation. 545/595 (91.6%) patients reaching EOT achieved SVR12. Overall, TF occurred in 61/606 patients (10.1%), with 11 discontinuing DAA before EOT. Suboptimal DAA was the only independent predictor of both non-SVR12 (AHR 2.52, 95%CI:1.24-5.12) and TF (AHR: 2.19; 95%CI:1.13-4.22).
Only 35.3% had access to HCV treatment. Despite excellent rates of SVR12 rates (91.6%), only 21% (545/2,607) of our HIV-HCV co-infected patients are cured.
Journal Article
Association of the Endobiont Double-Stranded RNA Virus LRV1 With Treatment Failure for Human Leishmaniasis Caused by Leishmania braziliensis in Peru and Bolivia
Cutaneous and mucosal leishmaniasis, caused in South America by Leishmania braziliensis, is difficult to cure by chemotherapy (primarily pentavalent antimonials [Sbv]). Treatment failure does not correlate well with resistance in vitro, and the factors responsible for treatment failure in patients are not well understood. Many isolates of L. braziliensis (>25%) contain a double-stranded RNA virus named Leishmaniavirus 1 (LRV1), which has also been reported in Leishmania guyanensis, for which an association with increased pathology, metastasis, and parasite replication was found in murine models. Here we probed the relationship of LRV1 to drug treatment success and disease in 97 L. braziliensis-infected patients from Peru and Bolivia. In vitro cultures were established, parasites were typed as L. braziliensis, and the presence of LRV1 was determined by reverse transcription-polymerase chain reaction, followed by sequence analysis. LRV1 was associated significantly with an increased risk of treatment failure (odds ratio, 3.99; P = .04). There was no significant association with intrinsic SbV resistance among parasites, suggesting that treatment failure arises from LRV1-mediated effects on host metabolism and/or parasite survival. The association of LRV1 with clinical drug treatment failure could serve to guide more-effective treatment of tegumentary disease caused by L. braziliensis.
Journal Article
The Clinical Significance of Vancomycin Minimum Inhibitory Concentration in Staphylococcus aureus Infections: A Systematic Review and Meta-analysis
Background. Emerging data suggest that vancomycin may be less effective against serious methicillin-resistant Staphylococcus aureus (MRSA) infections with minimum inhibitory concentration (MIC) values at the higher end of the susceptibility range. The purpose of this review is to examine the strength of these associations. Methods. All relevant studies pertaining to treatment outcomes or mortality associated with vancomycin MIC were retrieved from the medical literature from January 1996 through August 2011 and analyzed according to Cochrane guidelines. Results. Of the 270 studies identified, 48 studies were reviewed, with 22 studies included in the final meta-analysis. Vancomycin MIC was significantly associated with mortality for MRSA infection irrespective of the source of infection or MIC methodology (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.14—2.37; P < .01). This mortality association was predominantly driven by bloodstream infections (BSIs; OR, 1.58; 95% CI, 1.06—2.37; P = .03) and isolates with a vancomycin MIC of 2 μg/mL by Etest (OR, 1.72; 95% CI, 1.34—2.21; P < .01). Vancomycin MIC was significantly associated with treatment failure irrespective of source of infection or MIC methodology (OR, 2.69; 95% CI, 1.60—4.51; P < .01). Conclusion. High vancomycin MIC was associated with a higher mortality rate in MRSA BSI. Thus, institutions should consider conducting Etest MICs on all MRSA BSI isolates. Although these data highlight concerns about vancomycin, currently, there are no data to support better survival rates with alternative antibiotics. Data are sorely needed to determine whether other agents can remedy these outcomes observed with vancomycin for MRSA infections with elevated vancomycin MIC values.
Journal Article
Predicting early endodontic treatment failure following primary root canal treatment
Background
Understanding when and why endodontic treatments fail could help clinicians make prognoses and thus improve treatment outcomes. This study was aimed to assess potential predictors of early endodontic treatment failure. We explored factors contributing to the failure of initial root canal treatment were explored, with a specific emphasis on evaluating the influence of the time elapsed since the initial treatment.
Methods
This retrospective cohort study enrolled 1262 patients who sought endodontic treatment at our department and 175 patients were included for analysis. Potential causes of endodontic treatment failure were investigated, such as inadequate obturation quality, inadequate coronal status, the presence of additional untreated canals, anatomical complexity, instrument separation, iatrogenic perforation, cracks, and endodontic-periodontal lesions. The patients were divided into “short-term” and “long-term” groups depending on the time that had passed since the initial treatment (i.e., < 5 and > 10 years, respectively). The causes of failure in the short-term and long-term group were analyzed and compared using logistic regression analyses. Subgroup analysis was performed according to the number of years since the initial treatment in the short-term group to further investigate the association between the time and cause of failure (i.e., < 1, 2, 3, and 4 years, respectively).
Results
Untreated additional canals were present in 21.7% of all cases, and in 36.9 and 6.4% of cases in the short-term and long-term groups, respectively. Multivariable analysis showed that the presence of untreated additional canals was significantly associated with short-term compared to long-term failure. Untreated additional canals were also associated with endodontic failure within 1, 2, 3, and 4 years.
Conclusions
The presence of untreated additional canals was a predictor of endodontic failure within 5 years following initial root canal treatment. To optimize long-term prognosis, it is important to detect and treat all root canals during the initial treatment.
Journal Article
FKS Mutant Candida glabrata: Risk Factors and Outcomes in Patients With Candidemia
Background. Echinocandins are recommended for Candia glabrata candidemia. Mutations in the FKS1 and FKS2 genes are associated with echinocandin resistance. Few studies have assessed risk factors for FKS mutant isolates and outcomes in patients receiving micafungin treatment. Methods. Patients with C. glabrata bloodstream infection admitted to a large, tertiary care hospital between 2009 and 2012 were included in this study. For each isolate, FKS1 and FKS2 genes were sequenced to identify mutations. Risk factors for FKS mutations and treatment outcomes in patients receiving an echinocandin were assessed using multivariate logistic regression. Results. Seventy-two patients were included in the study of which 13 (18%) had an FKS mutant isolate. The only significant predictor for FKS mutations was prior echinocandin exposure (odds ratio [OR], 19.9; 95% confidence interval [CI], 4.7–84.7; P ≤ .01). Treatment failure occurred in 17 (30%) of 57 patients who received an echinocandin and was more common in patients with FKS mutants (6 of 10; 60%) compared with non-FKS mutants (11 of 47; 23%). Underlying gastrointestinal disorder (OR, 4.7; 95% CI, 1.1–20.9; P = .04) and prior echinocandin exposure (OR, 8.3; 95% CI, 1.7–40.4; P ≤ .01) were independent predictors of echinocandin treatment failure. Treatment response and echinocandin minimum inhibitory concentrations varied among specific FKS mutations. Conclusions. FKS mutations were identified in 18% of 72 patients with C. glabrata candidemia. Common risk factors for FKS mutant isolates included previous echinocandin exposure, which also influenced response rates.
Journal Article
Sporothrix brasiliensis Treatment Failure without Initial Elevated Itraconazole MICs in Felids at Border of Brazil
Cat-transmitted sporotrichosis caused by Sporothrix brasiliensis is an emerging zoonosis in Latin America. Because treatment of feline sporotrichosis is often not effective, we sought to determine whether treatment failure results from S. brasiliensis strains that have existing elevated MICs for itraconazole, the primary treatment for this disease. During 2021-2023 at the triple border region of Brazil, Paraguay, and Argentina, 108 S. brasiliensis strains were isolated from felines before antifungal treatment. The main clinical manifestation was cutaneous disseminated sporotrichosis (61%), which was the only form resulting in sporotrichosis-induced deaths (61%). We conducted antifungal susceptibility testing for 9 antifungal compounds, evaluating for both mycelial and yeast phases. MIC levels were low for most antifungal agents but were higher in the mycelial phase than in the yeast phase, especially for voriconazole and isavuconazole. We conclude that the varying clinical manifestations of sporotrichosis and large differences in mortality rates were not caused by elevated itraconazole MICs.
Journal Article